JP2010519224A - Fixed drug ratio for the treatment of hematopoietic cancer and proliferative diseases - Google Patents

Abstract

A method for treating cancer or a blood proliferative disorder in a subject is provided.
Provided herein are methods for treating cancer by administering a pharmaceutical composition comprising a fixed, non-antagonistic molar ratio of cytarabine and anthracycline. Such methods are particularly useful for the treatment of patients suffering from advanced cancer or proliferative diseases.
[Selection] Figure 1A

Description

RELATED APPLICATIONS This application is a benefit of US Application No. 60 / 901,772 filed February 16, 2007, and US Application No. 60 / 965,196 filed August 17, 2007. Each of which is incorporated herein by reference in its entirety.

  The present invention relates to methods of delivering therapeutic combinations and improving therapeutic efficacy. More particularly, the present invention relates to the delivery of a fixed ratio combination of cytarabine and an anthracycline such as daunorubicin.

  In vitro studies have shown that anti-tumor activity can be enhanced when cytotoxic drugs are used in combination. This has led to the use of drug combinations in hospitals for many years, and as a result, cytotoxic drug combinations are now standard in many forms of cancer chemotherapy. New anticancer drugs are typically initially introduced into patients as a single drug. The maximum tolerated dose is determined for one drug before the second drug is added and the dose of one or both drugs is adjusted based on toxicity. Typically, more active or effective drugs are used at maximal doses and other drugs are titrated in increasing doses until the dose is reduced and dose limiting toxicity defines the maximum tolerated dose for the combination. As a result, the development of most combination regimens is empirically determined based on tolerability. However, in vitro, where the molar ratio of drugs used in the combination can be controlled, the drug combination that provides synergy in one ratio is simply additive or antagonistic in the other ratio (Mayer, LD et al., Mol. Cancer Ther. (2006) 5: 1844-1863). When individual free drugs are administered in chemotherapy “cocktails”, each drug is treated differently by the body, resulting in a change in the distribution and excretion of each drug, resulting in a period of time or Can produce drug ratios that are suboptimal or ineffective for most of the time. The observation that the in vitro synergistic activity of antineoplastic drugs depends on the specific drug ratio suggests that the in vivo and clinical activity of the combination may be enhanced by maintaining the synergistic ratio To do. In this way, the development of a unique combination chemotherapy regimen can be based on the most effective ratio rather than empirically based on toxicity.

  Combination chemotherapy including cytidine analogs and anthracyclines has been well studied for the treatment of various cancers or blood proliferative disorders. Anthracycline drug cocktails, such as the cytidine analogs cytarabine and daunorubicin, have demonstrated some efficacy in patients with hematologic malignancies. See, for example, Tallum et al., Blood (2005) 106: 2243. Since 1973, cytarabine in combination with anthracyclines has been the standard first-line therapy for acute myeloid leukemia (AML), and other regimens are compared against it. Currently, the standard treatment for AML is that of cytarabine and anthracyclines administered in the classic “7 and 3” regimen where cytarabine is administered for 7 consecutive days and daunorubicin is administered for the first 3 days of that 7 days. It is a combination.

  Cytarabine (cytosine arabinoside, Ara-C or 1-β-D-arabinofuranosylcytosine) is an antineoplastic agent specific for the cell cycle phase, mainly in the cell during the S-phase of cell division. Adversely affect. In the cell, cytarabine is converted to cytarabine-5′-triphosphate (ara-CTP), an active metabolite. Although the mechanism of action is not fully understood, ara-CTP is thought to act primarily through inhibition of DNA polymerase. Incorporation into DNA and RNA may also contribute to cytarabine cytotoxicity. Cytarabine is cytotoxic to a variety of proliferating mammalian cells in culture.

  Daunorubicin hydrochloride is a hydrochloride salt of an anthracycline cytotoxic antibiotic produced by the Streptomyces coeruleorubidus strain. Daunorubicin has antimitotic and cytotoxic activity through several proposed mechanisms of action. Daunorubicin forms a complex with DNA by intercalation between base pairs. It inhibits topoisomerase II activity by stabilizing the DNA-topoisomerase II complex and prevents the religation part of the ligation-religation reaction catalyzed by topoisomerase II. The result is single and double stranded DNA breaks. Daunorubicin can also inhibit polymerase activity, affect the regulation of gene expression, and create free radical damage to DNA. Daunorubicin has an antitumor effect against a broad spectrum of animal tumors, both transplanted or naturally occurring.

Although the combination of these two drugs administered as a drug cocktail offers certain advantages, there are various drawbacks that limit their therapeutic use. For example, administration of a free drug cocktail is typically cleared rapidly before one or all drugs reach the disease site. If individual drugs in a cocktail are optimally effective only within a narrow ratio of each other, quickly clearing one drug and not clearing the other can reduce the overall efficacy of the combination while increasing toxicity. As individual drug dosages are increased to achieve higher therapeutic effects, this can sometimes lead to increased toxicity. Attempts to improve activity and reduce toxicity can also include longer infusion times. For example, according to 1 hour high dose (1 g / ^{m 2} / day) by slow bolus multiplied, or continuous continuous infusion for 7 days 1 day, lower, more typical dose (100 to 200 mg / ^{m 2} / day ) And the current administration of cytarabine. Administration with such long infusions results in complexity, increased length of stay and cost, and increased risk of infusion complications.

  The addition of other drugs such as 6-thioguanine or etoposide to improve results, and changes in doses or dosing schedules have been studied, but progress has been made while anthracyclines and cytarabine have been used for 30 years Continues to be the basis for standard induction treatment in AML. Thus, there is a need for more effective and better tolerated induction and / or consolidation therapy to substantially improve overall survival in disease in addition to reduced toxicity.

  Drug delivery regimens for these agents that allow sustained delivery of non-antagonistic drug ratios, as confirmed herein, reduce their effectiveness without increasing their toxicity This is highly desirable because it allows the number of doses to be reduced without it. Improvements in such dosing regimens may also allow patients to be administered doses that are more effective than those allowed by other dosing regimes that are otherwise limited by toxicity.

  In one aspect, provided herein is a method for treating cancer or a blood proliferative disorder in a subject, the method comprising a fixed, non-antagonistic molar ratio of cytarabine and an anthracycline such as daunorubicin. Administering an article to the subject, wherein the cytarabine: anthracycline ratio is maintained at a non-antagonistic ratio in plasma for at least about 4 hours. In another aspect, the fixed, non-antagonistic molar ratio is maintained for at least about 8 hours, at least about 16 hours, or at least about 24 hours. The anthracycline can be daunorubicin or mitoxantrone. In a particular embodiment, the anthracycline is daunorubicin. Typically, cytarabine and anthracyclines are stably associated with one or more delivery vehicles. Encapsulation in the delivery vehicle allows more than one drug to be delivered to the disease site in a coordinated manner, thereby ensuring that the drug is present at the disease site in a non-antagonistic ratio. This result is achieved either when the drugs are encapsulated together in a delivery vehicle or separately in a delivery vehicle that is administered so that the non-antagonistic ratio is maintained at the disease site. Will be. The PK is controlled by the delivery vehicle itself so that coordinated delivery is achieved (when the pharmacokinetics (PK) of the delivery system is comparable). In one aspect, the delivery vehicle is a liposome.

  In another aspect, provided herein is a method for treating cancer or a blood proliferative disorder in a subject, said method comprising a fixed pharmaceutical composition comprising a non-antagonistic molar ratio of cytarabine and anthracycline. Wherein the composition is administered intravenously. In some embodiments, the pharmaceutical composition is administered for at least about 30 minutes and less than about 8 or 12 hours. In certain embodiments, the pharmaceutical composition is administered in about 90 minutes. In another aspect, the pharmaceutical composition is administered on an outpatient basis. The anthracycline can be daunorubicin, idarubicin or mitoxantrone. In a particular embodiment, the anthracycline is daunorubicin.

In one aspect, provided herein is a method of treating such a disease in a subject in need of treating cancer or a blood proliferative disorder, the method comprising a fixed, non-antagonistic molar ratio of cytarabine and anthracycline. Administering to the patient, wherein cytarabine is administered at a low dose of less than 250 mg / m ² / day in less than 3 hours. In certain embodiments, cytarabine is administered at about 100~180mg / ^{m 2} / day in less than 3 hours. In another aspect, the low dose cytarabine is administered in about 90 minutes.

  In one aspect, provided herein is a method for reducing the toxicity of a cytarabine / anthracycline combination chemotherapeutic agent in a subject, which method stably binds to a fixed, non-antagonistic molar ratio of cytarabine and anthracycline. Administration of a pharmaceutical composition comprising a delivery vehicle to the patient, wherein toxicity resulting from administration of the composition is the same amount of cytarabine and anthracycline when not present in the delivery vehicle Lower than toxicity due to administration of In certain embodiments, the decrease in toxicity is measured as a decrease in non-hematopoietic toxicity, such as mucositis or hair loss. Such a reduction in toxicity can now lead to a reduction in hospital stay, supportive care, reduced morbidity and / or induction mortality, especially in patients over 60 and more specifically in patients over 75. .

  In the methods provided herein, the fixed, non-antagonistic molar ratio of cytarabine and anthracycline can be between about 25: 1 and about 1: 1. In a particular embodiment, the fixed, non-antagonistic ratio of cytarabine and anthracycline is about 5: 1. Typically, a fixed, noncompetitive ratio of cytarabine and anthracycline combination is encapsulated in liposomes.

  In some embodiments, the cancer is advanced blood cancer. The advanced blood cancer may be acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), or acute promyelocytic leukemia (APL). In one aspect, the blood proliferative disorder is myelodysplastic syndrome (MDS). Sometimes the cancer is a recurrent cancer. The subject can have previously received at least one anti-tumor regimen. In one aspect, the patient has failed or is refractory to one or more anti-tumor regimens. Sometimes the previous anti-tumor regimen is a multidrug regimen. In one aspect, the previous anti-tumor regimen consists of cytarabine with or without anthracycline.

  In an additional aspect, provided herein is such therapy in a subject in need of post-remission therapy for cancer or a blood proliferative disorder, the method comprising a fixed, non-antagonistic molar ratio of cytarabine and anthracycline. Administering a pharmaceutical composition to the patient, wherein the post-remission therapy is administered for less than 18 months after the same or different treatment. In certain embodiments, post-remission therapy is administered less than 6 months after the same or different treatment. In additional embodiments, post-remission therapy is administered to patients with relapsed AML, ALL, or APL. In one aspect, post-remission therapy is composed of cytarabine with or without anthracyclines.

In an additional aspect, provided herein is such therapy in a subject in need of first line therapy for cancer or a blood proliferative disorder, the method comprising a fixed, non-antagonistic molar ratio of cytarabine and anthracycline. Administering to the patient, wherein cytarabine is administered at a low dose of less than 3 hours and less than 250 mg / m ² / day. In certain aspects, first line therapy is provided to high risk patients, preferably elderly high risk patients. In another aspect, cytarabine is administered to high-risk patients at about 100 mg / m ² / day or less.

  Also contemplated is the use of a pharmaceutical composition comprising a fixed non-antagonistic molar ratio of cytarabine and anthracycline, wherein the cytarabine: anthracycline ratio is indicative of a cancer or blood proliferative disorder as disclosed herein. To treat the affected patient, maintain a non-antagonistic ratio in plasma for at least about 4 hours. In another aspect, provided herein is the use of a disclosed pharmaceutical composition comprising a fixed, non-antagonistic molar ratio of cytarabine and anthracycline for the preparation of a medicament for treating cancer or a blood proliferative disorder, The fixed, non-antagonistic molar ratio is maintained in plasma for at least about 4 hours to treat patients suffering from cancer as disclosed herein.

FIG. 1 shows the plasma drug concentration after administration of cytarabine and daunorubicin encapsulated in liposomes and the sustained, fixed non-antagonistic molar ratio of cytarabine: daunorubicin in plasma. A. Mean concentration of cytarabine and daunorubicin in the patient's plasma up to 7 days after the 5th day infusion of CPX-351 at 24 units / m ² (CPX-351 dosing cycle on days 1, 3 and 5) (LC− Concentration measured by MS / MS; each line represents a single patient; N = 3). FIG. 1 shows the plasma drug concentration after administration of cytarabine and daunorubicin encapsulated in liposomes and the sustained, fixed non-antagonistic molar ratio of cytarabine: daunorubicin in plasma. B. Molar ratio of cytarabine and daunorubicin in patient plasma (concentration measured by LC-MS / MS; each line is a single patient) up to 24 hours after the 5th day infusion of 24 units / m ² of CPX-351 N = 3). FIG. 1 shows the plasma drug concentration after administration of cytarabine and daunorubicin encapsulated in liposomes and the sustained, fixed non-antagonistic molar ratio of cytarabine: daunorubicin in plasma. C. Molar ratio of cytarabine and daunorubicin in the patient's plasma (concentration measured by LC / MS / MS; each line is single) from day 5 to day 48 after infusion of 57 units / m ² of CPX-351 Represents patient; N = 3).

  Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents, patent applications, published patent applications and other publications referred to herein are hereby incorporated by reference in their entirety. If the definitions described in this section are contrary to or otherwise inconsistent with the definitions described in patents, patent applications, published patent applications and other publications incorporated herein by reference, The definitions set forth in this section supersede the definitions incorporated herein by reference.

As used herein, “a” or “an” means “at least one” or “one or more”.
For cytarabine and anthracyclines, the non-antagonistic molar ratio in vitro was between 25: 1 and about 1: 1, where a 5: 1 molar ratio was found to be optimal. Any suitable anthracycline can be used. The anthracycline can be daunorubicin, idarubicin or mitoxantrone. In a particular embodiment, the anthracycline is daunorubicin.

  The development of CPX-351 (cytarabine: daunorubicin) liposome injection is 1) defining a non-antagonistic ratio of two active moieties, cytarabine and daunorubicin, using a cell-based screening assay, and 2) this after intravenous administration Based on designing liposomal drug carriers to maintain the ratio. This ratio was not based on the empirical dosing regimen currently used for cytarabine and anthracyclines.

  Provided herein are methods for delivering fixed, non-antagonistic molar ratios of cytarabine and anthracyclines to enhance anti-tumor activity while providing the benefits of rapid administration. Briefly, the non-antagonistic ratio of these chemotherapeutic agents was determined in vitro using cell-based screening techniques. When these same ratios are administered separately as free drug cocktails (eg, conventional water-based pharmaceutical formulations without liposome delivery), the drugs are distributed and excreted independently of each other, resulting in continuous Such ratios are not maintained because they result in ratios that vary. By using drugs encapsulated in liposomes, the methods provided herein allow for the maintenance of non-antagonistic ratios after prolonged administration. Liposome formulations control the individual pharmacokinetics of each drug, thereby delivering each drug in the correct ratio by maintaining a non-antagonistic ratio.

  Typically, sustained delivery requires higher drug dosages in order to maintain therapeutically effective levels of the drug in plasma and eventually at the tumor or disease site. Such high doses are administered for long periods of time, often over a day, and require long-term hospitalization and / or reliance on long-term infusion protocols, which increases the risk of complications such as infections or pump upsets . Another disadvantage is that toxicity due to higher doses may prevent reaching optimal plasma levels.

  CPX-351 is a liposomal formulation with a fixed 5: 1 molar ratio of cytarabine and daunorubicin, which has shown enhanced efficacy in cell culture and in vivo models (Mayer, LD, et al., Mol. Cancer). Ther. (2006) 5: 1844-1863). Cytarabine (4-amino-1-[(2R, 3S, 4R, 5R) -3,4-dihydroxy-5- (hydroxymethyl) oxolan-2-yl] pyrimidin-2-one or 1β-arabinofuranosylcytosine And daunorubicin ((8S, 10S) -8-acetyl-10-[(2S, 4S, 5S, 6S) -4-amino-5-hydroxy-6-methyl-oxan-2-yl] oxy- Any suitable source of 6,8,11-trihydroxy-1-methoxy-9,10-dihydro-7H-tetracene-5,12-dione or daunomycin servidin may be utilized.

Any suitable delivery vehicle that allows sustained delivery of the cytarabine: daunorubicin combination in a fixed, non-antagonistic molar ratio provided herein can be utilized. In one aspect, a single delivery vehicle is utilized. In other embodiments, multiple active agents are delivered in separate delivery vehicles that maintain the desired non-antagonistic ratio of the agent. In some embodiments, liposomal formulations may be utilized. Liposomes are designed for sustained delivery of encapsulated drugs to a tumor or disease site at a non-antagonistic ratio. In one aspect, cytarabine and daunorubicin are stably associated with one or more liposomes. Typically, liposomes have an average diameter of less than 300 nm and sometimes less than 200 nm. In one example, the nominal size of these liposomes is approximately 100 nm and sterilization is achieved by filtration through a 0.2 μm filter. In a particular embodiment, the liposome membrane is composed of a 7: 2: 1 molar ratio of distearoylphosphatidylcholine (DSPC), distearoylphosphatidylglycerol (DSPG) and cholesterol (CHOL). In one example, the liposomes are prepared by a liposome method derived from a water-in-oil type, and the extruded liposomes are suspended in phosphate buffered sucrose, pH 7.4. In a particular embodiment, the cytarabine to lipid ratio is about 1: 1.5 to 1: 2.6 and the daunorubicin to lipid ratio is about 1: 1.77 to 1: 12.5. Preferably, the cytarabine to lipid ratio is about 1: 2 and the daunorubicin to lipid ratio is 1:10. Exemplary delivery vehicles include Torchilin et al. (Eds.), Liposomes: A Practical Approach (Oxford University Press 2nd Edition. 2003); Gregoriadis, Liposome Technology 3rd Edition. It is not limited to them. Any suitable means for encapsulating the drug combination in the liposome can be utilized. In a particular embodiment, cytarabine and daunorubicin are encapsulated in liposomes, by which cytarabine is passively encapsulated in preformed liposomes, and daunorubicin is encapsulated based on copper gluconate / triethanolamine The procedure is used to actively accumulate inside the liposomes with high trapping efficiency. See, for example, co-pending PCT application No. WO 07/076117.

The methods provided herein are useful in any subject, particularly a human suffering from cancer or an advanced blood tumor or disease. Cancer includes any malignant cell with abnormal, uncontrolled growth. Such cells have several unique properties such as uncontrolled proliferation, immortality, metastatic potential, rapid growth and proliferation rate, and certain typical morphological features. Often the cancer cells are in the form of a tumor, but such cells may also be present alone in the mammal or may be non-neoplastic cancer cells, such as leukemia cells. Some cells detect the presence of one tumor or multiple tumors (eg, by clinical or radiological means), are derived from within a tumor, or from another biological sample (eg, from a tissue biopsy) Testing) cells, measuring blood markers indicative of cancer (eg, CA125, PAP, PSA, CEA, etc.) and / or detecting genotypes indicative of cancer (eg, TP53, ATM, etc.) Cancer is confirmed by any of several methods, including but not limited to. The term “hematopoietic tumor” refers to a tumor or cancer of the blood. As used herein, the term “advanced hematopoietic tumor” refers to a malignant tumor that is recurrent or refractory to one or more previous anti-tumor regimens. The hematopoietic tumor can be leukemia or lymphoma. Such tumors include acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), acute promyelocytic leukemia (APL), precursor and mature B cell neoplasms, chronic lymphocytic leukemia (CLL), plasma Cell neoplasm, chronic myelogenous leukemia (CML), multiple myeloma, Hodgkin lymphoma, non-Hodgkin lymphoma, myelodysplastic syndrome (MDS), myelodysplastic and myeloproliferative disease, chronic myelomonocytic leukemia (CMML), Examples include polycythemia vera, precursor and mature T cell neoplasms, T cell leukemia and lymphoma, mycosis fungoides, and Sezary syndrome. For example, Table 71.3 (World Health Organization lymphoma of lymphoma physiology in the genus of Greer et al. (Ed.), Wintrobe's Clinical Hematology (Lippincott Williams & Wilkins 11th edition (2003)). Please refer to. Tumors treated using the compositions provided herein include those in adult and pediatric patients. The composition can be utilized in induction and maintenance therapy. The disclosed compositions are also useful for related blood disorders such as myelofibrosis and amyloidosis resulting from light chain disease. More specifically, AML can include those with recurrent genetic abnormalities (regardless of blast percentage): t (8; 21) (q22; q22), (AML1 / ETO) ), Abnormal bone marrow eosinophils and inv (16) (p13q22) or t (16:16) (p13; q22), AML with (CBFβ / MYH11), t (15; 17) (q22; q12), acute promyelocytic leukemia with (PML / RARα) and variants and AML with 11q23 (MLL) abnormalities; multicellular lineage dysplasia such as MDS or MDS / MPD below (minimum 20% blasts) AML with dysplasia in at least 50% of cells in two or more myeloid lineages without previous MDS or MDS / MPD; AML or MDS that are linked (minimum 20% blasts), for example, types associated with alkylating agents / radiotherapy and types associated with topoisomerase II inhibitors (some may be lymphoid), and AML that cannot be classified elsewhere.

  The methods disclosed herein provide for sustained delivery of a fixed, non-antagonistic molar ratio of cytarabine and daunorubicin. For example, the non-antagonistic molar ratio of cytarabine: daunorubicin in plasma is maintained for at least about 4 hours, at least about 8 hours, at least about 12 hours, at least about 16 hours, and often up to at least about 24 hours after a single dose of the drug combination. Is done. Moreover, the sustained concentration of the drug combination encapsulated in liposomes in plasma is higher than the drug concentration of the free cocktail drug combination in plasma.

“Maintained” or “maintained” means that the drug: drug ratio changes less than 5 times, preferably less than 4 times, less than 3 times, and most preferably less than 2 times.
The disclosed methods are also therapeutically effective in treating recurrent cancers. “Relapsed cancer” refers to a cancer that has relapsed after a complete or partial remission in response to previous treatment. Recurrence can be defined in any way, including clinical cell reappearance or regrowth as detected by clinical, radiological, or biochemical assays, or by increased levels of cancer markers. Prior treatments can include, but are not limited to, chemotherapy, biological or hormonal therapy, radiation therapy, and bone marrow transplantation.

  In certain embodiments, a patient treated by the methods provided herein is a patient who has been previously treated with other therapies, has progressed after other therapies, or is resistant to other therapies. For example, the patient can be treated with the methods provided herein after having received or become resistant to any chemotherapy or biological therapy. For example, some patients may have previously been given one or more of the following drugs: cyclophosphamide, prednisone, methylprednisolone, imatinib, ifosfamide, methotrexate, leucovorin, vincristine, cytarabine, etoposide, dexamethasone, doxorubicin, Daunorubicin, asparaginase, 6-mercaptopurine, 6-thioguanine, carboplatin, fludarabine, gemtuzumab, arsenic trioxide, tretinoin, idarubicin, mitoxantrone, alemtuzumab, chlorambucil, cladribine, rituximab, pentostatin, hydroxyurea, interferon alpha B Nelarabine and azacitidine.

  In certain embodiments, a patient treated by the methods provided herein has been treated with other therapies, has progressed after other therapies, or is resistant to other therapies, and such therapies Was administered within a period of less than 18 months, or more specifically within a period of less than 12 months, or even more clearly within a period of less than 6 months. This is true even if the patient has relapsed during this period.

The methods provided herein can also be utilized as first line therapy for previously untreated cancer or blood cancer. In certain aspects, first line therapy is administered to high-risk patients, more specifically high-risk elderly patients. In certain embodiments, high-risk patients are given a dose of cytarabine of about 100 mg / m ² / day or less.

  Responses to the disclosed therapeutic methods include any clinically apparent favorable change in hematological cancer or abnormal disease state. Such responses include complete or partial remission, increased overall survival and increased survival without progression. Disease response is assessed by any appropriate means. For example, in the case of AML, ALL, and myelodysplastic syndrome, complete remission is up to ≧ 1000 / dL of peripheral blood neutrophils, platelets up to 100,000 / dL, and 5% without Auel bodies. Requires normalization of normal medulla with less than blasts. A response is considered partial if the Auer bodies are present with less than 5% blasts. Normalization of peripheral blood neutrophils and platelet counts is seen, but if 6-25% of blasts persist in the bone marrow, the response is considered partial. The duration of the overall response demonstrates relapse or progressive disease from the first time the response criteria meet complete response (CR) or partial response (PR) (anything recorded for the first time) It can be measured up to the first point in time. Response duration can be measured from the first time a CR or PR metric is met to the first time that a relapse or progressive disease is objectively demonstrated.

  The pharmaceutical compositions provided herein are administered to any suitable subject, preferably a human subject suffering from cancer. Preferably, the pharmaceutical composition of the present invention is administered intravenously. The dosage of the delivery vehicle formulation will depend on the opinion of the administering physician based on the age, weight, and condition of the patient. Individual judgment may vary from the physician's point of view, but surprisingly uses substantially shorter durations at substantially lower doses than those currently used for standard treatment protocols including cytarabine and daunorubicin Thus, it has been found that sufficient dosages of the fixed ratio combination of the present invention can be obtained. As previously mentioned, the “7 and 3” regimen has cytarabine administered 24 hours a day for 7 consecutive days and daunorubicin by IV for the first 3 days of 7 consecutive days. This means that the patient must be connected to a continuous infusion pump for cytarabine administration rather than IV infusion. It is possible that these pumps preloaded with cytarabine equivalent to the entire 7 days do not run smoothly and release all that corresponds to the 7 days at a time, or no drug at all. As mentioned, the use of such pumps increases the risk of inadequate drug delivery. Patients using the pump must also be checked daily in the hospital so that the pump can be checked, which increases hospital costs and patient inconvenience. Compositions of the invention with a fixed ratio of cytarabine: daunorubicin or other non-antagonistic ratios of fixed anthracyclines have a much shorter period, typically 12 hours or less, 8 hours or less, and more typically 3 It has been found that it can be administered in less than an hour. The achievement of this degree, in particular an infusion period of 8 hours or less, allows administration on an outpatient basis. It also allows administration by IV infusion rather than by an infusion pump. These parameters further reduce the risk of patients with infusion reactions.

  Therefore, the method of the present invention requiring an IV infusion time of less than 12 hours, preferably less than 8 hours, more preferably less than 3 hours is advantageous from the viewpoint of patient convenience and safety.

  A pharmaceutical composition comprising a delivery vehicle of the present invention is prepared according to standard techniques and contains glycoproteins for increased stability, such as albumin, lipoproteins, globulins, etc., water, buffered water, 0.9% It may contain physiological saline, 0.3% glycine, 5% dextrose and the like. These compositions may be sterilized by conventional, known sterilization techniques. The resulting aqueous solution may be packaged for use or filtered under aseptic conditions and lyophilized, the lyophilized preparation being combined with a sterile aqueous solution prior to administration. The composition is pharmaceutically acceptable auxiliary substances such as sodium acetate, sodium lactate, sodium chloride, potassium chloride, such as pH adjusters and buffers, osmotic pressure adjusters, etc., necessary to approach physiological conditions, It may contain calcium chloride and the like. Moreover, the delivery vehicle suspension may contain a lipid protectant that protects the lipid from free radicals and lipid peroxidation damage during storage. Lipophilic free radical quenchers such as water-soluble iron-specific chelators such as alpha-tocopherol, ascorbyl palmitate and ferrioxamine are suitable.

  The concentration of the delivery vehicle in the pharmaceutical formulation can vary widely from less than about 0.05% by weight, usually from about 2-5% or at least 2-5% to as much as 10-30% Depending on the particular mode of administration, it will be selected primarily by liquid volume, viscosity, etc. For example, the concentration may be increased to reduce the fluid load associated with treatment. Alternatively, a delivery vehicle composed of inflamed lipids may be diluted to a low concentration to reduce inflammation at the site of administration. In the case of diagnosis, the amount of delivery vehicle administered will depend on the specific label used, the disease state being diagnosed, and the judgment of the clinician.

The results of the methods of the invention are typically more effective than those provided by the “standard treatment” protocol. In the “standard treatment protocol”, cytarabine is administered at a dosage level of 100-200 mg / m ² / day by continuous infusion over 7 days and daunorubicin is administered at a dose of 45-60 mg / m ² for the first 3 days of this dosing schedule. IV.

  The safety of the procedure can be adjusted by assessing side effects such as hair loss, cellulitis, injection site or leaching reaction, or mucositis. Mucositis can be measured by oral or anal inflammation or ulceration; by esophageal ulceration or esophagitis; nausea, vomiting or diarrhea; and anorexia. Side effects are attenuated by avoiding prolonged tube placement.

  The following examples are presented to illustrate the invention, but not to limit it.

Example 1
In vivo study with CPX-351 The toxicity of CPX-351 (cytarabine: daunorubicin) liposome infusion was studied in rats and dogs given single and repeated doses (3 doses repeated every other day for 2 days). It has been.

Single dose study In a single dose study (Table 1), CPX-351 was administered by intravenous infusion over 1 hour and animals were observed for 14 days. “Vehicle control” consisted of liposomes containing copper gluconate but no drug. There were no drug-related deaths in rats given a single dose of CPX-351. Various hematological parameters and dose-related changes in spleen and hepatic extramedullary hematopoiesis were observed in both male and female medium and high dose groups on day 15 compared to control rats. The non-toxic dose (NOAEL) for a single dose of CPX-351 in rats was cytarabine 10 mg / kg: daunorubicin 4.4 mg / kg. In dogs receiving a single dose of CPX-351, between 8-10 days after administration, high dose (6 mg / kg cytarabine: 2.64 mg / kg daunorubicin) male and female animals and medium dose due to poor condition (3 mg / kg cytarabine: 1.32 mg / kg daunorubicin) females were killed before termination. Prior to lethality, these dogs showed a significant decrease in food intake and weight loss, as well as a significant decrease in white blood cell and platelet counts. Histological findings in dogs that were terminated early included decreased lymphoid cell density, atrophy of the spleen and thymus, and necrosis / bleeding of the gastrointestinal tract. There were no drug-related clinical signs in animals given the low dose (1.5 mg / kg cytarabine: 0.66 mg / kg daunorubicin) or vehicle control. There were no drug-related changes in hematology, clinical chemistry, blood clotting, urinalysis, or macroscopic evaluation in animals that survived to scheduled lethality. There was no microscopic evidence of decreased lymphoid cell density and spleen atrophy in medium dose males. Whole blood copper concentrations on day 2 (approximately 24 hours after treatment) increased in a dose-related manner in all animals receiving CPX-351, but returned to normal levels by days 8-15 It was.

Multiple dose study multiple dose study (dose and schedule of 1, 3, 5 and 22, 24 and 26 days; [Table 2]), the mortality associated with drug in both rats and dogs were observed. In rats, the underlying pathology leading to early termination or death in groups 3 (10 mg / kg cytarabine: 4.4 mg / kg daunorubicin) and 4 (15 mg / kg cytarabine: 6.6 mg / kg daunorubicin) is significant, Or severe bone marrow hematopoietic cell density reduction and spleen and thymus lymphoid cell density reduction / atrophy. In animals that died early or were killed, necrosis of the gland and crypt epithelium of the large and small intestinal mucosa was seen. When compared to the mean control values obtained on day 34 (7 days after the last dose), a moderate decrease in drug-related WBC count was seen in group 2 (5 mg / kg cytarabine: 2.2 mg / kg daunorubicin) ) Found in rats. All high-dose (Group 4) animals assigned to the recovery group were found dead or were killed early (days 10-16), so the reversibility of the cytotoxic effect of CPX-351 is Then I could not prove.

  Following the first dosing cycle, all dogs in the high dose CPX-351 group (Group 5; 3 mg / kg cytarabine: 1.32 mg / kg daunorubicin) were found dead (2 males) or 7-10 days He was killed because of poor eye condition. Two dogs (Group 4, 1 male and 1 female) in the medium dose group were killed due to poor condition on day 12. Possible causes of death in dogs found dead and major potential distress in unscheduled dogs are severe bone marrow cell density decline and / or moderate to severe Intestinal (duodenum, jejunum, ileum, cecum, colon and rectum) crypts / gland necrosis and lymphoid atrophy of the lymphoid tissue associated with the intestine.

  Peripheral blood leukocyte depletion was observed on day 33 (6 days after the last dose of CPX-351 or free drug) group 3 (1 mg / kg cytarabine: 0.44 mg / kg daunorubicin) and group 6 (free cytarabine 2 mg / kg and free daunorubicin 0.88 mg / kg). These leukopenia were the result of a marked decrease in the absolute and relative numbers of neutrophils, monocytes and eosinophils. In addition, mild to moderate reductions in hemoglobin, hematocrit and platelet counts were observed in Groups 3 and 6. Group 4 animals receiving only one cycle of drug treatment showed values (with the exception of RDW and HDW) similar to the mean hematological values of day 33 controls. After a 22-day recovery period (day 56), hematologic values including RDW and HDW of group 4 animals are comparable to those of control animals, and the hematological effect of CPX-351 is reversible Suggested.

  After the recovery period, there were no drug-related histopathological changes in the surviving group 4 dogs (except for one animal showing moderate splenic lymphoid necrosis), which was related to CPX-351 administration The findings suggested that it was partially or completely reversible. In tissue from control (Group 1), vehicle (Group 2), low dose CPX-351 (Group 3) and comparative free drug treated (Group 6) animals, drug-related histopathological changes are seen There wasn't.

  Total blood copper concentrations in animals that ended early (Day 7-9; Group 5) increased slightly. By day 33, the surviving and treated dog's copper levels returned to normal levels, suggesting that copper was drained from the blood of dogs fed CPX-351.

Example 2
Phase 1 clinical trial
Physical, chemical and pharmaceutical information CPX-351 is a fixed combination liposomal formulation of the antineoplastic drugs cytarabine and daunorubicin. The two drugs are present inside the liposomes at a 5: 1 molar ratio that was shown to have non-antagonistic activity in preclinical studies. The liposome membrane is composed of 7: 2: 1 molar ratio of distearoyl phosphatidylcholine, distearoyl phosphatidylglycerol and cholesterol. These liposomes have a nominal diameter of approximately 100 nm and are suspended in sucrose-phosphate-buffer, pH 7.4. Sterilization is achieved by filtration through a 0.22 μm filter.

  CPX-351 is supplied in a disposable 10 mL glass vial as a 5 mL sterile, pyrogen-free, purple opaque suspension, and similarly as a 20-25 mL suspension in a 50 mL glass vial. May be provided. CPX-351 is stored frozen (−20 ° C.) and thawed at room temperature for 60 minutes prior to dilution and administration. CPX-351 may also be lyophilized for storage and resuspended prior to administration. This dispersion is diluted with normal saline or dextrose for injection prior to intravenous administration to the patient.

  CPX-351 (cytarabine: daunorubicin) liposome injections in 10 mL disposable vials each provided 25 mg cytarabine and 11 mg daunorubicin. Each milliliter of thawed formulation is listed in Table 3 below.

Clinical Research—Starting Dose For cytotoxic antineoplastic agents, the customary starting dose for the first trial in humans is calculated on the basis of body surface area (mg / m ² ) and is generally the rodent LD ₁₀ ( 1 / 10th of this dose if not significantly more toxic to non-rodents, or "Toxic Dose Low" in most sensitive species (drug induced in hematological, chemical, clinical or morphological parameters) The lowest dose that produces a pathological change that is given) is given as 1/3 of the dose if it is not lethal and causes severe, irreversible toxicity. The rodent LD ₁₀ (based on cytarabine dose) is approximately 10 mg / kg (60 mg / m ² ), so that 1/10 is equal to 6 mg / m ² . Dog TDL was 1 mg / kg (20 mg / m ² ), but twice this dose (40 mg / m ² ) was lethal. Thus, 1/3 of 20 mg / ^{m 2} is equal to 6.7 mg / ^{m 2,} using the 1/2 (1/6 of the highest non-lethal dose) for safety, therefore, for this calculation the starting dose based is 3 mg / ^{m 2.} This is the CPX-351 formulation is cytarabine 3 mg / ^{m 2} and daunorubicin 1.32 mg / ^{m 2.}

The schedule AML standard remission induction regimen generally consists of 3 days anthracycline antibiotics and 5-7 days cytarabine. A 1, 3 and 5 day dosing schedule that is close to the standard dosing schedule is used. CPX-351 was administered on days 1, 3 and 5 of each introductory course. If there was evidence of anti-leukemic effects and persistent leukemia in the 14-day bone marrow, a second induction course was allowed.

Infusion time An acute infusion-related reaction (eg, flushing of the face, shortness of breath, headache, chills, low back pain, chest tightness and / or hypotension) has been observed in a large-scale study of a patient receiving liposomal chemotherapeutic agents Yes. In most patients, once the infusion is complete, these responses are alleviated in a few hours to a day. In some patients, the response is mitigated by slowing the infusion rate. The following table (Table 4) compares the amount of lipid in several liposome products and in CPX-351. A 90 minute infusion time was selected based on this information.

Dose escalation and level CPX-351 active part, cytarabine and daunorubicin have 30+ years experience and toxicity is well recognized. There has also been considerable experience with liposomal encapsulation of cytotoxic drugs (eg, Doxil®, Daunoxom®, Myoset®), and in general the dose of the active moiety when encapsulated is toxic Is not significantly different from the free drug. Because of this experience and prior to treatment initiation, we have observed toxic or pharmacodynamic effects because exposure to sub-optimal doses of therapeutics to patients with fast disease progression is undesirable in Phase 1 trials We proposed an accelerated escalation schedule with dose doubling (early phase) and 50% dose increase (late phase), followed by dose escalation that progressed by 33% increase (see Table 5A).

Dose escalation in patients receiving CPX-351 liposome injection will occur in two phases. The initial phase begins with 3 units / m ² (1 unit = 1 mg cytarabine and 0.44 mg daunorubicin) for a single patient cohort up to dose level 5 (48 u / m ² ) or as defined below Escalate by dose doubling until evidence of leukemia or pharmacodynamic (PD) effect is seen:
・ Decrease in bone marrow cell density (> 50% reduction, with blast reduction)
And / or possibly an event emerging from non-hematological treatment (≧ grade 2 <DLT), possibly or clearly related to CPX-351.

If a PD effect is seen, a second patient joins the cohort. If the patient also experiences a PD effect, dose escalation continues with a 33% increase with 3 patients per cohort. If the second patient has no PD effect, dose escalation continues with one patient per cohort and dose doubling in the early phase and a 50% increase in the late phase. Late phase escalation begins at dose level 6 (72 u / m ² ) with 50% dose escalation and one patient per cohort until the PD effect is seen as described above. When DLT is observed in the first subject during early or late phase escalation, up to 5 additional patients (not more than 6 patients) are added and the second patient experiences DLT Dose escalation will be stopped (see below). If no other patient experiences DLT, dose escalation continues with a 33% increase. If ≧ 2 patients treated at the specified dose level experience DLT, the MTD is considered already exceeded and an additional 3 patients are enrolled at the next lower dose level. Dose escalation to subsequent dose levels until the last patient at the previous level has been evaluated for at least 14 days after the last dose of each induction course; and there is no evidence of potential hematological DLT If not done.

  To date, as outlined in Table 5B below, dose escalation remains at 33% and has not been increased to a 50% increase.

Repeat patients on induction may receive a second induction course at the same dose as the first induction, if the bone marrow biopsy / puncture fluid at day 14 or around day 14 represents leukemia persistence. Intra-patient dose escalation is not allowed. If bone marrow biopsy / puncture fluid represents <20% cell density and <5% blasts, after 5-7 days if persistent leukemia is still unclear and still considered dysplastic Repeated bone marrow biopsy / puncture fluid must be obtained. Patients with dysplasia (<20% cell density and <5% blasts) are observed for hematopoietic recovery and toxicity until about day 42 of the study day or until the start of consolidation therapy. Patients with residual leukemia may receive a second induction if there is evidence of a substantial anti-leukemic effect after the first induction. If a second induction is administered, the patient will be followed up to about 42 days after the start of the second induction course.

For disease criteria AML, ALL, refractory anemia with excess blasts, or excess blasts during transformation, complete remission up to> 1000 / dL peripheral blood neutrophils, 100,000 / dL Normalization of normal marrow with more platelets and blasts with less than 5% Auel bodies is required. A response is considered partial if the Auel bodies are present with less than 5% blasts. Normalization is seen in peripheral blood neutrophils and platelet counts, but if 6-25% blasts persist in the bone marrow, the response is considered partial.

Reaction duration . Response duration is measured from the first time the metric for CR or PR is met to the first day that recurrent or progressive disease is objectively demonstrated.
Result . This study is a non-randomized, open label, single group, dose escalation phase 1 trial. The period of research registration up to now has taken about 18 months. All 33 previously treated subjects (22 men; 11 women), median age 62 years (24-81) were enrolled in the 10 cohort. The actual demographics and placement of the first 10 cohorts are summarized in Table 6 below:

As is typical for Phase 1 trials, patients in this Phase 1 population were patients who had no alternative treatment options and had previously received large amounts of treatment. The results of these leukemia patients at doses at which we began to achieve therapeutic responses are summarized in Table 7 below. In Table 7, the following abbreviations are used: “CR” represents complete remission; “PR” represents “partial remission”; “CRp” represents “complete remission with incomplete platelet recovery” (ie, , Could not achieve platelet recovery greater than or equal to 100,000 / μL by day 42); “BMT” represents “bone marrow transplant”; “PD” as Represents the pharmacodynamic (PD) effect as defined in:
・ Decrease in bone marrow cell density (> 50% reduction, with blast reduction)
And / or possibly an event emerging from non-hematological treatment (≧ grade 2 <DLT), possibly or clearly related to CPX-351.

As evidenced by the results, therapeutic response is observed with as little CPX-351 as 32 units / m ² being administered, surprisingly up to and including nearly 134 units / m ² Continued to be observed over multiple dose levels.

Example 3
CPX-351 Phase 1 Trial-Case Study The following is a case study of 5 patients treated in an ongoing CPX-351 Phase 1 trial.

Case Study 1- AML patients respond to CPX-351 even though they did not respond to previous customary 7/3 cytarabine / daunorubicin therapy: patient 02-011, age 62, diagnosed with AML in 2007 Men received early levlimid therapy from September to November 2007 and showed no response. In December 2007, the patient received a standard customary 7 + 3 cytarabine / daunorubicin treatment, but did not respond again. Bone marrow analysis on day 14 after initiation of conventional 7 + 3 cytarabine / daunorubicin treatment showed 5% cell density + 24% blasts. Patients are immediately registered in the CPX-351 Phase trials, it was given CPX-351 of January 2008 schedule that begins two days 1, 3 and 5 days in 134 units / ^{m 2.} Analysis of patient bone marrow after 15 days showed dysplasia (<10% cell density, <5% blasts).

Case Study 2- AML patients who have previously received high-dose treatment achieve a complete response after CPX-351 treatment: Patient 03-015, a 67-year-old woman was treated with idarubicin / cytarabine in May 2002, and 2002 From June to August received high dose ara-C (or cytarabine), consolidation treatment, also called HDAC. The patient achieved a complete response (CR) lasting 4 years and 8 months. The patient relapsed and was enrolled in the CPX-351 Phase 1 trial on October 29, 2007 and was given 134 units / m ² of CPX-351 on the 1, 3 and 5 day schedules. Patient bone marrow analysis after 15 days showed <10% cell density. The patient achieved a CR of 42 days after starting to take CPX-351. The only adverse effects recorded were gingival bleeding and grade 3 rash 10-15 days after CPX-351 was initiated.

Case Study 3- AML patients unable to receive conventional 7 + 3 cytarabine / daunorubicin therapy due to age, poor health and lack of expected resistance to highly cytotoxic therapeutics induced CPX-351 Achieve complete response with minimal adverse effects after therapy: Patient 03-008, for the prediction that a 74 year old woman is unable to withstand conventional therapy that is age and highly cytotoxic Received light prior treatment. The patient was treated with Zanestra from April 2004 to April 2006 and did not respond. From May 2006 to February 2007, she received induction therapy with Arsenic / Cytarabine and achieved a CR lasting 7 months. The patient relapsed and was given lintuzumab from March 2007 to April 2007 but did not respond. The patient was enrolled in the CPX-351 Phase 1 trial and received three doses of 43 units / m ² of CPX-351 starting on April 30, 2007. On day 35 after initiation of CPX-351 treatment, patient achieves CR (3% blasts); patient is further on consolidation therapy starting on day 52 after initial induction treatment (on days 1 & 3, administered 5 days I was given CPX-351. AML was not detectable 204 days after the initial CPX-351 treatment.

Case Study 4 - If not respond to 7 + 3 cytarabine / daunorubicin treatment or clofarabine / cytarabine therapy practice, AML patients were scheduled CPX-351 treatment after bone marrow transplantation: patient 02-008,49 year old male is customary 7 + 3 cytarabine / Daunorubicin treatment was given and showed no response. The patient was then given clofarabine / cytarabine treatment and again showed no response. Thereafter, the patient was enrolled in the CPX-351 Phase 1 trial and began taking PX-351 at 101 units / m ² on September 24, 2007. On day 15 after the patient's initial CPX-351 treatment, bone marrow analysis showed 5% cell density and 16% blasts, and a bone marrow transplant was scheduled for day 29. The only adverse effects reported were fatigue and grade 1 rash 8 days after the initial CPX-351 treatment. This patient demonstrated, among other things, the potential use of CPX-351 as a bone marrow pretreatment agent.

Case Study 5- ALL patients previously treated extensively achieved a complete response with CPX-351 treatment: Patient 01-002, 44-year-old female is on pre-treatment for hematopoietic stem cell transplantation from March to April 2006 Given in part cyclophosphamide / daunorubicin followed by dexamethasone / vincristine / L-asparagine, achieved a CR lasting 8 months. The patient was subsequently enrolled in a CPX-351 Phase 1 trial and started CPX-351 at 43 units / m ² on May 7, 2007. On day 12 after the initial infusion, bone marrow analysis showed <10% cell density and 0% blasts and a CR was recorded on day 43 after the initial CPX-351 treatment. This patient demonstrates, among other things, the potential use of CPX-351 in acute lymphoblastic leukemia.

Example 4
CPX-351 Phase 1 clinical trial- goal of pharmacokinetic (PK) analysis of pharmacokinetic study-cytarabine and daunorubicin and selected metabolites (Ara-U and daunorubicinol) after CPX-351 administration in leukemia patients ) To determine the pharmacokinetics of single and multiple doses.
• Collect preliminary information on overall exposure, dose balance, and accumulation of CPX-351 in cancer patients.
• If possible, establish a correlation between exposure intensity to CPX-351 ingredients and effects (safety and efficacy).

Plasma samples for PK sampling scheme PK analysis were collected on days 1, 3 and 5 of the first cycle. A blood sample (approximately 7 mL) was collected from the peripheral vein of the arm opposite the arm used for infusion and placed in a test tube containing ethylenediaminetetraacetic acid (EDTA) as an anticoagulant. Samples were collected during the initial introduction at the following times (corresponding to the start of injection).
• Before administration on day 1, 45 minutes during infusion (or midpoint of infusion) and 90 minutes (or at the end of infusion), then 2, 4, 6, 8, 12, and 24 hours corresponding to the start of infusion In.
• Before administration on day 3, at 45 and 90 minutes during infusion.
• Before administration on day 5, at 45 minutes (or midpoint of infusion) and 90 minutes (or at the end of infusion) during the infusion, then 2, 4, 6, 8, 12, 24, At 48, 72, 96, and 168 hours.

Pharmacokinetic analysis Plasma samples were analyzed for cytarabine, daunorubicin, and metabolites Ara-U and daunorubicinol by LC-MS / MS using a validated, specific high performance liquid chromatography mass spectrometry method It was. Plasma concentration-time profiles were generated for cytarabine and daunorubicin for each patient. Pharmacokinetic parameters were deduced from the plasma concentration-time profiles of all evaluable patients. Pharmacokinetic parameters that can be calculated by using the non-compartmental method and WinNonlin® Professional (Version 4.0 or higher) include, but are not limited to:
Cmax maximum observed concentration Tmax time of Cmax appearance λz elimination rate constant obtained from linear regression of concentration versus time data converted to natural body number (In) in final phase (only after administration on day 5) t1 / 2 Final half-life, calculated as In (2) / λz AUC (0-last) Plasma concentration-time curve from 0 o'clock to the time of quantifiable plasma concentration after the last dose, obtained by the linear trapezoidal method Lower area AUC (0 to infinity) Area under plasma concentration-time curve extrapolated from midnight to infinity CL (for cytarabine and daunorubicin on study day 5 only) Dose / AUC (0 to infinity) Computer Systemic clearance calculated by using the compartment method of pharmacokinetic analysis and metabolite placement kinetics and / or pharmacokinetic / pharmacodynamic modeling It may be subjected.

Descriptive statistics (mean, SD, CV%, median, minimum and maximum) can be used to summarize plasma concentrations and PK parameters, as well as other analyses, for each treatment cohort as appropriate. The pharmacokinetic analysis to date is summarized in FIG. FIG. 1A shows the mean plasma concentrations of cytarabine and daunorubicin from day 5 to day 7 among patients receiving 24 units / m ² of CPX-351 (N = 3). FIG. 1B shows the plasma molar ratio of cytarabine to daunorubicin up to 24 hours after the fifth day infusion between patients receiving 24 units / m ² of CPX-351 (N = 3). As seen in the figure, in all subjects analyzed, the 5: 1 molar ratio of cytarabine to daunorubicin was maintained at approximately 5: 1 for at least 24 hours. FIG. 1C shows the plasma molar ratio of cytarabine to daunorubicin up to 48 hours after the fifth day infusion between patients receiving 57 units / m ² of CPX-351 (N = 3). The graph of FIG. 1C clearly demonstrates that the molar ratio of cytarabine to daunorubicin was maintained at about 5: 1 in the patient's blood for at least about 48 hours.

Claims (21)

Use of a pharmaceutical composition comprising a fixed, non-antagonistic molar ratio of cytarabine and anthracycline in a method for treating a cancer or blood proliferative disorder in a subject comprising:
The method comprises intravenously administering the composition over a period of 12 hours or less;
The use, wherein the fixed ratio is maintained in plasma for at least 4 hours, and the fixed, non-antagonistic molar ratio of cytarabine and anthracycline is encapsulated in liposomes.   The use according to claim 1, wherein the composition is administered in 8 hours or less.   Use according to claim 2, wherein the composition is administered in 3 hours or less.   4. Use according to claim 3, wherein the composition is administered in 90 minutes or less.   5. Use according to any of claims 1 to 4, wherein the fixed non-antagonistic molar ratio of cytarabine to anthracycline is between about 1: 1 to 25: 1.   6. Use according to claim 5, wherein the fixed, non-antagonistic molar ratio is about 5: 1. Cytarabine is administered at 250 mg / ^{m 2} or less doses Use according to any one of claims 1 to 4.   Use according to any of claims 1 to 4, wherein the liposome comprises DSPC, DSPG and cholesterol.   9. Use according to claim 8, wherein the liposome comprises DSPC: DSPG: cholesterol in a molar ratio of 7: 2: 1.   Use according to any of claims 1 to 4, wherein the anthracycline is daunorubicin. 11. Use according to any of claims 10 wherein the dose of the composition is 32-134 units / m < ² > and 1 unit is 1 mg cytarabine and 0.44 mg daunorubicin.   Use according to any of claims 1 to 4, wherein the administration is by IV drip.   The cancer or blood proliferative disorder is an advanced blood cancer selected from acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML) and acute promyelocytic leukemia (APL), and the hematoproliferative disorder is Use according to any of claims 1 to 4, which is myelodysplastic syndrome (MDS).   Use according to any of claims 1 to 4, wherein the subject has previously received at least one anti-cancer regimen and / or has previously experienced remission.   15. Use according to claim 14, wherein the subject has experienced a recurrence within 18 months after the anti-cancer regimen.   16. Use according to claim 15, wherein the subject has experienced a recurrence within 6 months after the anti-cancer regimen.   Further comprising measuring the therapeutic effect as a function of increasing rate of complete remission and / or as a function of prolonged duration of complete remission and / or prolonged time to progression and / or prolonged survival. 4. Use according to any of 4.   18. Use according to claim 17, wherein the therapeutic effect is greater than that obtained when cytarabine and anthracycline are administered in a standard treatment protocol.   Use according to any of claims 1 to 4, further comprising measuring an improved safety result as a reduction in non-hematopoietic toxicity.   20. Use according to claim 19, wherein the non-hematopoietic toxicity is mucositis and / or hair loss.   20. Use according to claim 19, wherein the safety result is greater than that obtained when cytarabine and anthracycline are administered in a standard treatment protocol.

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